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Phytochemical and Biological Investigation of Immature Conifer

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Phytochemical and Biological Investigation of Immature Conifer Phytochemical and Biological Investigation of Immature Conifer Cones for Antibacterial and Modulatory Activity against Multidrug-resistant and Methicillin-resistant Staphylococcus aureus Thesis presented by Eileen Catherine Jean Smith for the degree of Doctor of Philosophy Centre for Pharmacognosy and Phytotherapy The School of Pharmacy University of London 2006 ProQuest Number: 10105105 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10105105 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 This thesis describes research conducted in the School of Pharmacy, University of London between April 2002 and January 2006 under the supervision of Dr. Simon Gibbons and Professor Elizabeth Williamson. I certify that the research described is original and that any parts of the work that have been conducted by collaboration are clearly indicated. I also certify that 1 have written all the text herein and have clearly indicated by suitable citation any part of this dissertation that has already appeared in publication. ,.lc^/\ 9 /i Signature Date - 2 - ABSTRACT Antibiotic resistance by pathogenic bacteria is a major problem both in hospitals and in the community. Of particular concern is methicillin-resistant Staphylococcus aureus (MRSA), many strains of which have acquired resistance to most antibiotics. Another mode of resistance is by means of an efflux pump and many S. aureus strains have acquired pumps which confer multidrug-resistance by effluxing many different compounds out of the cell. There is an urgent need to find new antibacterials and new ways to fight these resistant strains. The rationale for this study is that since cones are essential for reproduction in conifers, the immature cones are likely to contain compounds which protect against microbial invasion. Initial screening of cones from several conifer species identified anti-staphylococcal activity, which was greatest in the hexane extracts. Bioassay guided fractionation and structure elucidation using 1-D and 2-D NMR yielded several active diterpenes from Chamaecyparis lawsoniana, Chamaecyparis nootkatensis and Pinus nigra. These compounds showed activity (2 - 64 pg/ml) against multidrug-resistant and effluxing S. aureus clinical isolates, and against epidemic MRSA strains EMRSA-15 and -16, which are the major strains found in UK hospital MRSA bacteraemias. Some of the isolated diterpenes also demonstrated activity as potentiators of antibiotic activity. Ferruginol restored oxacillin sensitivity in EMRSA-15, and moderate activity in potentiating antibiotic activity against effluxing strains was also observed for ferruginol and totarol. Efflux inhibition assays suggested that these compounds were weak efflux pump inhibitors. This study demonstrates that compounds from immature conifer cones have good antibacterial activity and some modulatory activity against resistant strains of S. aureus. These compounds are worthy of further investigation, particularly as plants produce compounds which clinically relevant bacteria are unlikely to have previously encountered. 3 - TABLE OF CONTENTS Page ABSTRACT 3 TABLE OF CONTENTS 4 TABLE OF FIGURES 9 TABLE OF TABLES 11 ABBREVIATIONS 13 ACKNOWLEDGEMENTS 14 1.0 INTRODUCTION 15 1.1 THE PROBLEM OF RESISTANT BACTERIA 15 1.2 ANTIBACTERIALS 16 1.2.1 Triclosan 17 1.2.2 Silver Ions 19 1.3 ANTIBIOTICS 20 1.3.1 P-lactams 20 1.3.2 Glycopeptides 22 1.3.3 Macrolides 23 1.3.4 Tetracyclines 24 1.3.5 Fluoroquinolones 25 1.4 METHODS OF BACTERIAL RESISTANCE 26 1.4.1 Intrinsic Resistance 26 1.4.2 Acquired Resistance 27 1.4.3 Efflux Pumps 28 1.4.4 iS. Efflux Pumps 30 1.5 STAPHYLOCOCCI 32 1.5.1 Methicillin-resistant *S. (MRSA) 33 1.5.2. Penicillin Binding Protein (PBP2') 37 1.6 . NEW ANTIBIOTICS 39 1.7 MODULATION 41 - 4 - 1.8 CONIFERS 43 1.8.1 Chamaecyparis 43 1.8.2 Chamaecyparis lawsoniana 44 1.8.3 Chamaecyparis nootkatensis 44 1.8.4 'EûmohoXdûCvy0 Ï Chamaecyparis 46 1.8.5 Ch.Qm\s\iy o f Chamaecyparis 47 1.8.6 Pinus 51 1.8.7 Pinus nigra 51 1.8.8 Ethnobotany of Pines 52 1.8.9 Chemistry of Pines 52 1.8.10 Present Day Use of Conifer Compounds 55 1.8.11 Conifer Oleoresin 57 1.9 TERPENES 59 2.0 MATERIALS AND METHODS 2.1 PHYTOCHEMICAL METHODS 63 2.1.1 Conifer Material 63 2.1.2 Solvent Extraction 63 2.1.3 Thin-layer Chromatography (TEC) 64 2.1.4 Preparative Thin Layer Chromatography (PTLC) 65 2.1.5 Vacuum Liquid Chromatography (VLC) 6 6 2.1.6 Biotage"^^ Flash Chromatography 67 2.1.7 Solid Phase Extraction (SPE) 67 2.1.8 Size Exclusion Chromatography 6 8 2.1.9 High Performance Liquid Chromatography (HPLC) 69 2.2 SPECTROSCOPIC METHODS 70 2.2.1 Nuclear Magnetic Resonance (NMR) 70 2.2.1.1'HNMR 71 2.2.1.2'^CNM R 72 2.2.1.3 Two-dimensional spectra 72 2.2.1.4 Correlation Spectroscopy (COSY) 72 2.2.1.5 Heteronuclear Single Quantum Coherence (HSQC) 73 Spectroscopy 2.2.1.6 Heteronuclear Multibond Coherence (HMBC) 73 Spectroscopy 5 - 2.2.1.7 Nuclear Overhauser Effect Spectroscopy (NOESY) 73 2.2.2 Infra-red Spectroscopy and Polarimetry 74 2.2.3 Gas Chromatography-Mass Spectrometry (GC-MS) 74 2.3 BIOLOGICAL METHODS 75 2.3.1 Minimum Inhibitory Concentration (MIC) Assay 75 2.3.2 Modulation Assay 76 2.3.3 S. aureus Strains used in MIC and Modulation Assays 77 2.3.4 Ethidium Efflux Assay 78 3.0 RESULTS 79 3.1 PRELIMINARY SCREENING 79 3.2 EXTRACTION OF COMPOUNDS FROM CHAMAECYPARIS 82 LAWSONIANA 3.3 PHYTOCHEMICAL CHARACTERISATION OF COMPOUNDS 8 6 FROM CHAMAECYPARIS LAWSONIANA 3.3.1 CL-001 (Ferruginol) 86 3.3.2 CL-002 (Pisiferol) and CL-003 (5-Epipisiferol) 93 3.3.3 CL-004 (Formosanoxide) 101 3.3.4 CL-005 (4p-Hydroxygermacra-l(10),5-diene) 107 3.3.5 CL-006 (^raw5-Communic acid) 111 3.3.6 CL-007 (Torulosal) 118 3.3.7 CL-008 (Oplopanonyl acetate) 123 3.4 EXTRACTION OF COMPOUNDS FROM CHAMAECYPARIS 127 NOOTKATENSIS 3.4 PHYTOCHEMICAL CHARACTERISATION OF COMPOUNDS 130 FROM CHAMAECYPARIS NOOTKA TENSIS 3.5.1 CN-001 (Totarol) 130 3.5.2 CN-002 (7a-Hydroxytotarol) 135 3.5.3 CN-003 (Sempervirol) 141 3.5.4 CN-004 (Sugiol) 145 3.6 PINUSNIGRA 150 3.6.1 Preliminary Screening of Six Pinus Species 150 3.6.2 Extraction of PN-001 from «/gra 152 3.6.3 PN-001 (Isopimaric acid) 153 6 - 4.0 MIC AND MODULATION ASSAYS - RESULTS 159 AND DISCUSSION 4.1 RESULTS OF ANTI-STAPHYLOCOCCAL MIC ASSAYS 159 4.2 RESULTS OF MODULATION ASSAYS 165 4.3 ASSAYS FOR POTENTIATION OF COMPOUND ACTIVITY 170 4.3.1 Results 170 4.3.2 Abietic Acid and Reserpine 171 4.3.3 Molecular Modelling 173 4.4 RESULTS OF EFFLUX INHIBITION ASSAYS 176 4.4.1 The Effect of Ferruginol on Efflux of Ethidium Bromide 176 4.4.2 The Effect of Totarol on Efflux of Ethidium Bromide 177 4.5 DISCUSSION 179 4.5.1 Ferruginol 179 4.5.2 Totarol 182 4.5.3 Sempervirol 187 4.5.4 Sugiol 187 4.5.5 Pisiferol, 5-Epipisiferol and Formosanoxide 188 4.5.6 /rfl«5 -Communic Acid 189 4.5.7 4(3-Hydroxygermacra-l(10),5-diene 190 4.5.8 Isopimaric Acid and Abietic Acid 191 4.5.9 Oplopanonyl Acetate and Torulosal 192 4.6 STRUCTURE ACTIVITY RELATIONSHIPS 193 4.6.1 Phenol and Isopropyl Groups 194 4.6.2 Lipophilicity and SARs 195 4.6.3 Oxidation State of Functional Groups 197 4.6.4 Pisiferol Epimers and Formosanoxide 199 4.6.5 Potentiation of Antibiotic Activity - SARs 201 5.0 PEDICULICIDE ASSAYS AGAINST HUMAN LICE 208 5.1 INTRODUCTION 208 5.1.1 Head Lice Treatments 210 5.1.2 The Orlando Strain of Clothing Lice 213 5.2 METHODS 215 5.2.1 Filter Paper Disc Assay 215 5.2.2 Dip Method Pediculicide Assay 216 - 7 - 5.3 RESULTS 218 5.4 DISCUSSION 225 6.0 CONCLUSION 230 REFERENCES 232 PUBLICATIONS 267 - 8 - TABLE OF FIGURES Page Figure 1.2.2: Treatment of an MRSA infected leg ulcer with silver dressing 19 Figure 1.3.1: P-lactam ring with a fused thiazolidine ring 2 1 Figure 1.3.3: Erythromycin 23 Figure 1.3.4: Tetracycline 24 Figure 1.3.5: Norfloxacin 25 Figure 1.4.3: Drug efflux in Gram-positive and Gram-negative bacteria 30 Figure 1.5a: S. aureus 32 Figure 1.5b: S. aureus biofilm 32 Figure 1.5.1a: Methicillin 33 Figure 1.51.b: Headlines from selected articles on MRSA (2004/05) from 36 the London Evening Standard Figure 1.5.2: The precursors required for PBP2' activity 38 Figure 1.6: Linezolid 39 Figure 1.8.2a: C. lawsoniana 44 Figure 1.8.2b: C. lawsoniana shoot 44 Figure 1.8.3: C. nootkatensis shoot 45 Figure 1.8.5a: terpinen-4-ol and sabinene 43 Figure 1.8.5b: (+)-5-cadinene, (-)-p-curcumene and nootkatene 48 Figure 1.8.5c: Ferruginol, pisiferic acid and pisiferdiol 48 Figure 1.8.5d: Nootkastatin 2 and quercetin 49 Figure 1.8.5e: Chamaecydin 49 Figure 1.8.5f: Chamalignolide 50 Figure 1.8.6a: P.
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